Design and synthesis of biotinylated Hexylselen as a probe to identify KGA allosteric inhibitors by a convenient biomolecular interaction assay

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2498-2502. doi: 10.1016/j.bmcl.2019.07.014. Epub 2019 Jul 9.

Abstract

Hexylselen is a novel submicromolar dual KGA/GDH inhibitor, which demonstrates potent inhibition of cancer cells with minimal toxicity. To further investigation its mechanism of action, we designed and synthesized its biotinylated derivative 2 as a novel probe. From commercially available starting material, 2 was obtained in 6 steps with 13.4% overall yield. It is notable that this practical synthetic route give a template for the preparation of unsymmetrical di-benzo[d][1,2]selenazol-3(2H)-ones. Based on probe 2, we developed a novel biomolecular interaction assay for convenient and reliable test of KGA allosteric inhibitors and confirmed that hexylselen as an allosteric inhibitor of KGA sharing the same binding pocket with BPTES but not with Ebselen via competitive experiments.

Keywords: Allosteric inhibitor; Biomolecular interaction assay; Hexylselen; K-type glutaminase; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Azoles / chemistry
  • Azoles / metabolism
  • Biotinylation
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Glutamate Dehydrogenase / antagonists & inhibitors
  • Glutamate Dehydrogenase / metabolism
  • Ketoglutarate Dehydrogenase Complex / antagonists & inhibitors*
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Kinetics
  • Protein Binding
  • Selenium / chemistry*

Substances

  • Azoles
  • Enzyme Inhibitors
  • Ketoglutarate Dehydrogenase Complex
  • Glutamate Dehydrogenase
  • Selenium